Hematopoietic stem cells are pluripotent cells present in the bone marrow, which divide to produce more specialized progenitor stem cells, i.e., lymphoid progenitors and myeloid progenitors. Cells that are differentiated from the lymphoid progenitors in the bone marrow and that are found in the peripheral blood include B cells and T cells. From B cells are generated plasma cells; from T cells are generated activated T cells. Similarly, the common myeloid progenitor stem cells produce the granulocytes/macrophage progenitor cells and the megakaryocyte/erythrocyte progenitor cells in the bone marrow. Cells differentiated from the granulocyte/macrophage progenitors that are present in the blood include neutrophils, eosinophils, basophils, monocytes and immature dendritic cells. Monocytes further give rise to mast cells, macrophages and dendritic cells that are present in tissue and lymph nodes. Cells differentiated from the megakaryocyte/erythrocyte progenitors include megakaryocytes and erythroblasts, which further differentiate into platelets and erythrocytes (red blood cells) in the blood.
A number of these hematopoietic lineage cells are secretory cells upon activation. For example, platelets, the smallest corpuscular components of human blood, are characterized by a diameter of about 2-4 micrometers, the absence of a nucleus, and a physiological number varying from 150,000 to 300,000 per cubic millimeter of blood. Platelets contribute to the complex, multistep, and highly regulated process of thrombus formation and arterial occlusive disorders, a leading cause of human morbidity. Platelets target and adhere to sites of vascular injury. At the sites of vascular injury, the platelets are activated and form aggregates that provide a provisional seal. Platelets preferentially release their granular contents at the site of injury, e.g., contributing to the subsequent growth and stability of thrombi in part through the release of von Willebrand factor (vWF), fibrinogen, and other coagulation proteins such as Factor V (Holt J. C., and Niewiarowski, S. 1985 Sem. Hematol. 22:151-163) from their alpha-granules. Activated platelets also release proteins that inhibit thrombolysis, chief among which is plasminogen activator inhibitor-1 (PAI-1). Over 90% of the circulating PAI-1 is stored in platelet alpha-granules (Booth, N. A et al, 1988 Brit. J. Haematol. 70:327-333), although much of this is in an inactive form (Declerck, P. J et al, 1988 Blood 71:220-225; Kruithof, E. K et al, 1987 Blood 70:1645-1653). Nonetheless, this pool of PAI-1 is thought to be one of the main reasons why platelet-rich thrombi are especially resistant to thrombolytic therapy (Booth, N. A et al, 1992 Ann. N. Y. Acad. Sci. 667:70-80; Fay, W. P. et al, 1994 Blood 83:351-356).
Paradoxically, platelets also contain or can bind small amounts of plasma-derived profibrinolytic proteins, including urokinase-type plasminogen activator (u-PA) and plasminogen (Fay, W. P et al, 1994 cited above; Lenich, C. et al, 1997 Blood 90:3579-3586; Jiang, Y et al. 1996 Blood 87:2775-2781; Holt, J. C., and Niewiarowski, S. 1980 Circulation 62:342a). However, these proteins are found at very low levels, and their activity is overwhelmed by the large amounts of PAI-1, which helps to stabilize nascent thrombi.
Recently, the effect of changing this balance in platelet fibrinolytic proteins has been described. Quebec Platelet Disorder (QPD) is a rare bleeding disorder not responsive to platelet transfusion, but responsive to anti-fibrinolytic agents, such as tranexamic acid (Hayward, C. P. et al, 1997 Blood 89:1243-1253; Hayward, C. P. et al, 1996 Blood 87:4967-4978; Hayward, C. P. et al, 1997 Brit. J. Haematol. 97:497-503). The etiology of QPD has been ascribed recently to ectopic expression of an excess of u-PA in megakaryocytes and platelets (Kahr, W. H. et al., 2001 Blood 98:257-265). QPD platelets contain predominantly activated two-chain urokinase (tcu-PA). The etiology for the bleeding diathesis may in part be due to local release of activated u-PA within thrombi leading to premature lysis. However, degradation of multiple platelet alpha-granular proteins, including vWF and Factor V, presumably by plasmin generated as a result of urokinase, may interfere with thrombus development as well.
There remains a need in the art for methods for harnessing the cellular mechanisms of platelets as well as other cells differentiated from hematopoietic progenitor cells for therapeutic, diagnostic and research purposes.